Saturated Fatty Acids Dampen the Immunogenicity of Cancer by Suppressing STING

Authors

Blake R Heath
Wang Gong
Hülya F Taner
Luke Broses
Kohei Okuyama
Wanqing Cheng
Max Jin
Zackary R Fitzsimonds
Andriana Manousidaki
Yuesong Wu
Shaoping Zhang
Haitao Wen
Steven B Chinn
Eric Bartee
Yuying Xie
James J Moon
Yu Leo Lei

Publication Date

4-25-2023

Journal

Cell Reports

Abstract

Oncogenes destabilize STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs), to promote immune escape. Despite the abundance of tumor-infiltrating myeloid cells, HNSCC presents notable resistance to STING stimulation. Here, we show how saturated fatty acids in the microenvironment dampen tumor response to STING stimulation. Using single-cell analysis, we found that obesity creates an IFN-I-deprived tumor microenvironment with a massive expansion of suppressive myeloid cell clusters and contraction of effector T cells. Saturated fatty acids, but not unsaturated fatty acids, potently inhibit the STING-IFN-I pathway in HNSCC cells. Myeloid cells from obese mice show dampened responses to STING stimulation and are more suppressive of T cell activation. In agreement, obese hosts exhibited increased tumor burden and lower responsiveness to STING agonist. As a mechanism, saturated fatty acids induce the expression of NLRC3, depletion of which results in a T cell inflamed tumor microenvironment and IFN-I-dependent tumor control.

Keywords

Mice, Animals, Squamous Cell Carcinoma of Head and Neck, Fatty Acids, Interferon Type I, Myeloid Cells, Head and Neck Neoplasms, Tumor Microenvironment

DOI

10.1016/j.celrep.2023.112303

PMID

36952341

PMCID

PMC10514241

PubMedCentral® Posted Date

October 2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes